The purpose of this study is to develop a new approach to managing severe myocardial ischemic injury that occurs during a cardiac operation. This will be achieved by focusing on one aspect of myocardial ischemia-reperfusion (I-R) injury, namely myocyte sodium (Na) influx and consequent loss of ionic homeostasis. Na influx is an early event that putatively leads to myocardial calcium (Ca) influx, contractile dysfunction, mitochondrial injury, and cell death. This lab has found three methods (I-ischemic preconditioning, 2-Na/H exchange inhibition, and 3-reperfusion with a warm cardioplegia solution [controlled reperfusion]) that each eliminate myocyte Na content gain due to moderate l-R injury (cardioplegic arrest) in a porcine model. An intriguing pilot study in isolated rat hearts showed that two of these methods (preconditioning and Na/H exchange inhibition) when used simultaneously have additive beneficial effects on post-ischemic contractile function. The proposed study will measure reperfusion arrhythmias, contractile function mitochondrial function, and myocyte ion content in order to define the effects of severe I-R injury in rat and pig hearts. The goal of this study is to determine if three methods, with putatively independent but inter-related mechanisms of action, will work additively to protect the heart from severe I-R injury as defined by biochemical, functional, histologic, and electrophysiologic variables. The specific aims of the proposed study are as follows: Aim 1: Define the mechanisms of three methods for myocardial protection (Na/H exchange inhibition, mitochondrial K+ATP channel opening [pharmacologic preconditioning], and controlled reperfusion) in a clinically relevant, intact porcine heart model of severe regional I-R injury. These data will serve as baseline data for Aim 4. Aim 2: Measure the effects of the three methods for myocardial protection on post-ischemic systolic and diastolic function, coronary vascular resistance, myocyte and mitochondrial ion content, and mitochondrial function in an isolated blood perfused rat heart model of severe global ischemia. Aim 3: Test for the postulated beneficial interactions between pharmacologic preconditioning (diazoxide), NalH exchange inhibition (cariporide), and controlled reperfusion in a blood perfused rat heart model of I-R injury. Aim 4: Determine if the best combination of methods, as defined in aim #3, provides better protection than each method used individually in pig hearts. Better protection will be defined by irnproved myocyte and mitochondrial ion homeostasis, irnproved regional mechanical function, fewer reperfusion arrhythmias, superior protection of mitochondrial function, and smaller infarcts in hearts subjected to severe regional I-R injury.